Journal Article

Disease-associated astrocyte epigenetic memory promotes CNS pathology

Li, Zhaorong, Srun, Lena, Rone, Joseph M, Rothhammer, Veit, Wheeler, Michael A, Clark, Iain C, Kenison, Jessica E, Flausino, Lucas E, Akl, Camilo Faust, Giovannoni, Federico, Lee, Hong-Gyun, Antel, Jack, Pernin, Florian, Charabati, Marc, Quintana, Francisco J, Chao, Chun-Cheih, Shin, Seung Won, Illouz, Tomer, Prat, Alexandre, Kleemann, Kilian L, Zandee, Stephanie E J, Lee, Joon-Hyuk, Piester, Gavin, Sanmarco, Liliana M

2024

Overview

Astrocytes play important roles in the central nervous system (CNS) physiology and pathology. Indeed, astrocyte subsets defined by specific transcriptional activation states contribute to the pathology of neurologic diseases, including multiple sclerosis (MS) and its pre-clinical model experimental autoimmune encephalomyelitis (EAE) . However, little is known about the stability of these disease-associated astrocyte subsets, their regulation, and whether they integrate past stimulation events to respond to subsequent challenges. Here, we describe the identification of an epigenetically controlled memory astrocyte subset which exhibits exacerbated pro-inflammatory responses upon re-challenge. Specifically, using a combination of single-cell RNA sequencing (scRNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), and cell-specific CRISPR/Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) used by the histone acetyltransferase p300 to control chromatin accessibility. ACLY p300 memory astrocytes are increased in acute and chronic EAE models; the genetic targeting of ACLY p300 astrocytes using CRISPR/Cas9 ameliorated EAE. We also detected responses consistent with a pro-inflammatory memory phenotype in human astrocytes ; scRNA-seq and immunohistochemistry studies detected increased ACLY p300 astrocytes in chronic MS lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, MS. These findings may guide novel therapeutic approaches for MS and other neurologic diseases.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Astrocytes / ATP citrate lyase / Central nervous system / Chromatin / Coenzyme A / CRISPR / Epigenetics / Experimental allergic encephalomyelitis / Histone acetyltransferase / Immunohistochemistry / Immunology / Immunoprecipitation / Inflammation / Multiple sclerosis / Neurological diseases / Pathology / Phenotypes / Transcription activation / Transposase